86
W. D. Brown, A. H. Gouliaev
PAPER
fied by sublimation (50–55 °C/0.2 mbar) to give 1.39 g of 9a as an
off-white solid. The solid was dissolved in EtOH (15 mL) and pre-
cipitated as the hydrochloride by addition of 12 M HCl (0.7 mL),
yielding 1.23 g (34%) pure 9a as a white powder.
1H NMR (DMSO-d6): = 7.81 (dd, 1 H, J = 8.5, 4.2 Hz), 7.91 (d, 1
H, J = 8.1 Hz), 8.10 (d, 1 H, J = 8.1 Hz), 8.57 (dd, 1 H, J = 8.5, 1.4
Hz), 9.10 (dd, 1 H, J = 4.2, 1.4 Hz).
13C NMR (DMSO-d6): = 120.9, 124.0, 124.4, 128.1, 131.0, 133.5,
135.7, 144.9, 152.4.
Method B: To mechanically stirred CF3SO3H (15 mL) at 0 °C was
slowly added 6 (1.8 mL, 15.3 mmol). The mixture was cooled to
–40 °C and dibromoisocyanuric acid (3.06 g, 10.7 mmol) was added
at such a rate that the temperature was kept between –40°C to –35
°C. The mixture was stirred at –40 °C to –35 °C for 1 h 40 min and
worked up as in Method A to yield 1.56 g (44%) of 9a; mp 235 °C
(dec.); Rf 0.51 (CH2Cl2–Et2O, 9:1).
1H NMR (DMSO-d6): = 7.86 (t, 1 H, J = 8.0 Hz),17 7.91 (dd, 1 H,
J = 8.6, 4.6 Hz), 8.13 (d, 1 H, J = 7.5 Hz), 8.25 (d, 1 H, J = 8.5 Hz),
8.81 (d, 1 H, J = 8.6 Hz), 9.16 (dd, 1 H, J = 4.58, 1.4 Hz).
Anal. Calcd for C9H5Br2N: C, 37.67; H, 1.76; Br, 55.69; N, 4.88.
Found: C, 37.37; H, 1.50; Br, 55.42; N, 4.84.
6-Bromoquinazoline (11)
To a solution of 7 (1.04 g, 8.5 mmol) in concd H2SO4 (8 mL) at r.t.
was added NBS (2.13 g, 12.0 mmol). The reaction mixture was
stirred for 15 h. Further NBS (1.13 g, 6.35 mmol) was added and the
mixture was stirred for another 6 h and worked up as described
above. Column chromatography (eluent: CH2Cl2–MeOH, 20:1)
yielded 450 mg (27%) of pure 11 as a white powder; mp 136–
138 °C; Rf 0.40 (CH2Cl2–MeOH, 20:1).
1H NMR (DMSO-d6): = 7.98 (d, 1 H, J = 9.0 Hz), 8.17 (dd, 1 H,
J = 9.0, 2.3 Hz), 8.45 (d, 1 H, J = 2.2 Hz), 9.35 (s, 1 H), 9.61 (s, 1
H).
13C NMR (DMSO-d6): = 121.6, 123.4, 126.1, 127.2, 131.7, 132.1,
138.7, 144.7, 149.4.
Anal. Calcd for C9H7BrClN: C, 44.20; H, 2.88; Br, 32.68; Cl, 14.50;
N, 5.72. Found: C, 43.89; H, 2.55; Br, 32.72; Cl, 14.48; N, 5.74.
13C NMR (DMSO-d6): = 120.6, 125.8, 130.0, 130.1, 137.7, 148.0,
155.4, 160.0.
5-Bromoquinoxaline (12)
To a solution of 8 (1.3 g, 10 mmol) in concd H2SO4 (10 mL) at r.t.
was added NBS (1.3 g, 13 mmol). The reaction mixture was stirred
for 20 min at r.t., 5.5 h at 60 °C and then worked up as described
above, with the exception that CH2Cl2 (3 100 mL) was used for
extraction and brine was added, until two separate phases were ob-
tained. Column chromatography gave 260 mg (12%) pure 12 as an
off-white powder; mp 65–67 °C; Rf 0.63 (CH2Cl2–Et2O, 9:1).
1H NMR (DMSO-d6): = 7.80 (t, 1 H, J = 8.0 Hz),17 8.14 (dd, 1 H,
J = 8.4, 1.1 Hz), 8.25 (dd, 1 H, J = 7.6, 1.1 Hz), 9.04 (d, 1 H, J = 1.7
Hz), 9.07 (d, 1 H, J = 1.7 Hz).
Anal. Calcd for C8H5BrN2: C, 45.96; H, 2.41; Br, 38.22; N, 13.40.
Found: C, 45.60; H, 2.04; Br, 38.31; N, 13.06.
Acknowledgement
The authors thank John Bertelsen, Tove Thomsen and Carina M.
Schmücker for technical assistance and associate professor Lars
Henriksen for valuable discussion.
13C NMR (DMSO-d6): = 123.5, 129.3, 130.1, 133.6, 139.6, 143.3,
146.5, 146.6.
References
(1) Iddon, B.; Wakefield, B. J. In Bromine Compounds; Price,
D.; Iddon, B.; Wakefield, B. J., Eds.; Elsevier: Amsterdam,
1988, 181–251.
Anal. Calcd for C8H5BrN2: C, 45.96; H, 2.41; Br, 38.22; N, 13.41
Found: C, 45.97; H, 2.13; Br, 38.18, N, 13.25.
(2) Encyclopedia of Reagents for Organic Synthesis; Paquette,
L. A., Ed.; Wiley: Chichester, 1995.
(3) Duan, J.; Zhang, L. H.; Dolbier, W. R. Jr. Synlett 1999, 1245.
(4) Osborn, A. R.; Schofield, K.; Short, L. N. J. Chem. Soc.
1956, 4191.
(5) Gordon, M.; Pearson, D. E. J. Org. Chem. 1964, 29, 329.
(6) Rey, M.; Vergnani, T.; Dreiding, A. S. Helv. Chim. Acta
1985, 68, 1828.
5,8-Dibromoisoquinoline (4)
To mechanically stirred concd H2SO4 (17 mL) at 0 °C was slowly
added 1 (2 mL, 17 mmol). The mixture was cooled to –25 °C and
NBS (6.97 g, 39.2 mmol) was added at such a rate that the reaction
temperature was kept between –25 °C to –20 °C. The mixture was
stirred at –20 °C to –15 °C for 1 h and then allowed to reach r.t. in
1 h, at which temperature it was stirred for another 1 h. Workup was
done as described above and column chromatography (eluent:
(7) Dewar, M. J. S.; Maitlis, P. M. J. Chem. Soc. 1957, 2521.
(8) Butler, J. L.; Forrest, L. B.; Gordon, M. Trans. Ky. Acad. Sci.
1977, 38, 15.
(9) Gottardi, W. Monatsh. Chem. 1968, 99, 815.
(10) Gottardi, W. Monatsh. Chem. 1969, 100, 42.
(11) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals; Pergamon: Oxford, 1988, 3rd ed., 105.
(12) Tochilkin, A. I.; Kovel’man, I. R.; Prokof’ev, E. P.;
Gracheva, I. N.; Levinskii, M. V. Chem. Heterocycl. Compd.
(Engl.Transl.) 1988, 24, 892.
CH2Cl2–EtOAc, 9:1
8:1) gave 3.88 g slightly impure 4. Further
purification by sublimation (90 °C/0.1–0.2 mbar) yielded 3.60 g
(76%) of pure 4 as a white powder; mp 113–115 °C; Rf 0.63
(CH2Cl2–EtOAc, 9:1).
1H NMR (DMSO-d6): = 7.94 (d, 1 H, J = 8.0), 7.98 (d, 1 H, J = 5.9
Hz), 8.07 (d, 1 H, J = 8.0 Hz), 8.79 (d, 1 H, J = 5.9 Hz), 9.49 (d, 1
H, J = 0.5 Hz).
13C NMR (DMSO-d6): = 118.8, 120.5, 121.4, 126.8, 132.3, 134.9,
135.5, 145.7, 151.5.
Anal. Calcd for C9H5Br2N: C, 37.67; H, 1.76; Br, 55.69; N, 4.88.
Found: C, 37.41; H, 1.58; Br, 55.98; N, 4.87.
(13) Kanbara, T.; Saito, N.; Yamamoto, T.; Kubota, K.
Macromol. 1991, 24, 5883.
(14) Saito, N.; Kanbara, T.; Nakamura, Y.; Yamamoto, T.;
Kubota, K. Macromol. 1994, 27, 756.
(15) Sidhu, G. S.; Thyagarajan, G.; Rao, N. Indian J. Chem.
1963, 1, 346.
(16) Hollstein, U.; Krisov, G. E. Org. Magn. Reson. 1980, 14,
300.
(17) This expected doublet of doublet was observed as a triplet
with the given coupling constant.
5,8-Dibromoquinoline (10)
To a solution of 6 (1 mL, 8.5 mmol) in concd H2SO4 (8.5 mL) at r.t.
was added NBS (3.47 g, 19.49 mmol). The reaction mixture was
stirred at r.t. for 8 h and worked up as described for 4 (sublimation
at 95 °C/1.5 mbar) to give 1.84 g. The slightly impure product was
further purified by recrystallization from heptane (30 mL) to give
1.42 g (61%) as a white powder; mp 126–128 °C. Rf 0.83 (CH2Cl2–
EtOAc, 9:1).
Synthesis 2002, No. 1, 83–86 ISSN 0039-7881 © Thieme Stuttgart · New York